This project is concerned with the structure and function of the protective mucus barrier in the large airways.[unreadable] Our work indicates that the layer should really be considered as two gels, one surrounding the cilia which we[unreadable] call the peri-ciliary gel layer (PGL) and the other flowing mucus layered upon it and moved by it. The gel[unreadable] surrounding the cilia and microvilli is a special gel formed by the epithelial mucins MUC1, 4 and 16, attached[unreadable] by their C-termini to these structures. Such a gel is called a grafted gel layer and it has special properties[unreadable] that control accessibility to the surface and its interaction with the layer above. The properties of the flowing[unreadable] mucus layer are controlled by two gel forming mucins termed MUC5B and MUC5AC. Our data both in cell[unreadable] culture and induced secretions suggests that MUC5B forms the basis of the normal flowing gel. However if[unreadable] the lung is irritated or provoked by acute infection a thick highly elastic gel enriched in MUC5AC is secreted[unreadable] by surface goblet cells. We hypothesise that this gel is important in the normal situation to help aid clearance[unreadable] by cough. During infection and/or chronic disease there is hyperplasia of goblet cells and an up-regulation of[unreadable] MUC5AC production. The aims of our project are, using a human bronchial epithelial cell line and normal[unreadable] and pathological sputum to characterize the properties of the PGL and to identify the molecular mechanisms[unreadable] underlying the MUC5AC-rich gel and the MUC5B flowing mucus. We further hypothesise that cough and flow[unreadable] are controlled by differing adhesion strengths and mechanisms between these gels and the PGL. If this[unreadable] adhesion is too strong , e.g. malfunctioning hydration mechanisms such as occur in CF then neither of the[unreadable] maechanisms will function effectively and stasis, infection and inflammation will ensue.[unreadable] Relevance to Public Health[unreadable] The airway is defended from chemical, biological and physical insult by mucus, a gel comprised of greater[unreadable] than 90% water and associated cations, the remainder being proteins and glycoproteins. Diseases affecting[unreadable] the lung e.g. chronic bronchitis, asthma and cystic fibrosis are associated with an enhanced mucus[unreadable] secretion. In the normal lung a 10-20u thick mucus blanket flows from the alveolus to the esophagus over a[unreadable] bed of cilia which beat in a 7u thick layer that was just thought to be water but our work indicates is a special[unreadable] protective gel. We now call this protective layer the peri-ciliary gel layer (PGC). The long term objective of[unreadable] this project is to understand how these two layers are maintained and work together to protect the lung and[unreadable] thus help design better therapies.